One of the most well-known and widely used of the classes of antibacterial agents is the class known as the beta-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the beta-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given beta-lactam antibiotic results because the microorganism produces a beta-lactamase. The latter substances are enzymes which cleave the beta-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when a beta-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a beta-lactamase inhibiting substance and a beta-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components.
Penicillanic acid 1,1-dioxide, its pharmaceutically-acceptable salts, and its esters readily hydrolyzable in vivo are potent inhibitors of microbial beta-lactamases. According to this invention there is provided a method for increasing the effectiveness of the cephalosporin antibiotic, 7-(D-2-[4-ethylpiperazin-2,3-dione-1-carboxamido]-2-[4-hydroxyphenyl]-acet amido)-3-([1-methyl-5-tetrazolyl]thiomethyl)-3-desacetoxymethylcephalospora nic acid and its pharmaceutically-acceptable salts, using said penicillanic acid 1,1-dioxide, pharmaceutically acceptable salts thereof, or esters thereof readily hydrolyzable in vivo. Additionally, according to this invention, there are provided pharmaceutical compositions, useful for treating bacterial infections in mammals, which comprise penicillanic acid 1,1-dioxide or a pharmaceutically acceptable salt thereof or an ester thereof readily hydrolyzable in vivo, and 7-(D-2-[4-ethylpiperazin-2,3-dione-1-carboxamido]-2-[4-hydroxyphenyl]aceta mido)-3-([1-methyl-5-tetrazolyl]thiomethyl)-3-desacetoxymethylcephalosporan ic acid or a pharmaceutically-acceptable salt thereof.
1,1-Dioxides of benzylpenicillin, phenoxymethylpenicillin and certain esters thereof have been disclosed in U.S. Pat. No. 3,197,466 and No. 3,536,698, and in an article by Guddal et al., in Tetrahedron Letters, No 9, 381 (1962). Harrison et al., in the Journal of the Chemical Society (London), Perkin I, 1772 (1976), have disclosed a variety of penicillin 1,1-dioxides and 1-oxides, including methyl phthalimidopenicillanate 1,1-dioxide, methyl 6,6-dibromopenicillanate 1,1-dioxide, methyl penicillanate 1-alpha-oxide, methyl penicillanate 1-beta-oxide, 6,6-dibromopenicillanic acid 1-alpha-oxide and 6,6-dibromopenicillanic acid 1-beta-oxide.